一个有效的计算协议,用于基于模板的的设计,以抑制涉及SARS-CoV-2蛋白质的相互作用
Akshay Chenna1, Wajihul Hasan Khan1,2, Rozaleen Dash1
1Department of Chemical Engineering, Indian Institute of Technology Delhi, New Delhi, India.
Proteins
|June 7, 2023
概括
研究人员设计了针对SARS-CoV-2RNA依赖RNA聚合酶 (RdRp) 复合物的新型抑制剂. 这种结构生物信息学方法成功地识别了阻断病毒复制必需蛋白质-蛋白质相互作用的.
科学领域:
- 结构生物信息学 结构生物信息学
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
背景情况:
- SARS-CoV-2 的RNA依赖RNA聚合酶 (RdRp) 复合体对于病毒复制和转录至关重要.
- 在RdRp复合体内高度保存的接口为抑制器设计提供了机会.
- 准蛋白质与蛋白质相互作用 (PPI) 是抗病毒开发的一个有前途的战略.
研究的目的:
- 应用结构生物信息学协议来设计SARS-CoV-2 RdRp复合体的抑制剂.
- 为了特别抑制核心子单元nsp12和辅助因子nsp7.7之间的相互作用.
- 为了验证设计的有效性和特征作为潜在的抗病毒药物.
主要方法:
- 使用分子动力学识别nsp7-nsp12复合体内的相互作用热点.
- 针对nsp7结合接口的大型类库的in-silico选. nsp7结合接口.
- 使用表面等离子体共振 (SPR),ELISA,细胞透和细胞毒性试验对类的表征.
主要成果:
- 两种类被确定为NSP7结合界面的高特异性.
- 体对nsp7 (Kd 133nM和167nM) 显示出强烈的结合亲和力,表现优于nsp12结合 (Kd 473nM).
- 一种可以显著抑制nsp7-nsp12复合 (IC50 25μM),具有良好的细胞透和低细胞毒性.
结论:
- 该研究提出了一个成功的概念验证,用于针对SARS-CoV-2 PPI的理性抑制剂设计.
- 开发的生物信息学方法可用于发现其他病毒蛋白相互作用的抑制剂.
- 已识别的具有作为治疗SARS-CoV-2感染的治疗剂的潜力.
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